ABSTRACT

Context The optimal duration of antimicrobial treatment for ventilator-associated
pneumonia (VAP) is unknown. Shortening the length of treatment may help to
contain the emergence of multiresistant bacteria in the intensive care unit
(ICU).

Objective To determine whether 8 days is as effective as 15 days of antibiotic
treatment of patients with microbiologically proven VAP.

Design, Setting, and Participants Prospective, randomized, double-blind (until day 8) clinical trial conducted
in 51 French ICUs. A total of 401 patients diagnosed as having developed VAP
by quantitative culture results of bronchoscopic specimens and who had received
initial appropriate empirical antimicrobial therapy were enrolled between
May 1999 and June 2002.

Intervention A total of 197 patients were randomly assigned to receive 8 days and
204 to receive 15 days of therapy with an antibiotic regimen selected by the
treating physician.

Main Outcome Measures Primary outcome measures—death from any cause, microbiologically
documented pulmonary infection recurrence, and antibiotic-free days—were
assessed 28 days after VAP onset and analyzed on an intent-to-treat basis.

Results Compared with patients treated for 15 days, those treated for 8 days
had neither excess mortality (18.8% vs 17.2%; difference, 1.6%; 90% confidence
interval [CI], −3.7% to 6.9%) nor more recurrent infections (28.9% vs
26.0%; difference, 2.9%; 90% CI, −3.2% to 9.1%), but they had more mean
(SD) antibiotic-free days (13.1 [7.4] vs 8.7 [5.2] days, P<.001). The number of mechanical ventilation–free days, the
number of organ failure–free days, the length of ICU stay, and mortality
rates on day 60 for the 2 groups did not differ. Although patients with VAP
caused by nonfermenting gram-negative bacilli, including Pseudomonas aeruginosa, did not have more unfavorable outcomes when
antimicrobial therapy lasted only 8 days, they did have a higher pulmonary
infection-recurrence rate compared with those receiving 15 days of treatment
(40.6% vs 25.4%; difference, 15.2%, 90% CI, 3.9%-26.6%). Among patients who
developed recurrent infections, multiresistant pathogens emerged less frequently
in those who had received 8 days of antibiotics (42.1% vs 62.0% of pulmonary
recurrences, P = .04).

Conclusions Among patients who had received appropriate initial empirical therapy,
with the possible exception of those developing nonfermenting gram-negative
bacillus infections, comparable clinical effectiveness against VAP was obtained
with the 8- and 15-day treatment regimens. The 8-day group had less antibiotic
use.

Figures in this Article

Hospitals and particularly intensive care units (ICUs) are faced with
the emergence and rapid dissemination of multiresistant bacteria.1- 4 In some
cases, the choice of potential therapies is limited or even nonexistent.5- 8 The response
to this challenge lies in a policy of prevention and better utilization of
antimicrobial therapy, notably shortening the duration and decreasing the
number of antibiotics given to ICU patients to contain the emergence and dissemination
of such pathogens.3,9- 12 Because
of its frequency and severity,13,14 nosocomial
pneumonia in patients requiring prolonged mechanical ventilation represents
1 of the principal reasons for the prescription of antibiotics in the ICU.15 At present, most experts recommend that treatment
of ventilator-associated pneumonia (VAP) last 14 to 21 days in most cases,
even though these recommendations remain largely empirical, primarily because
of an absence of prospective randomized controlled studies specifically devoted
to this issue.16,17 This recommendation
is justified, in theory, by the high risk of infection relapse after a shorter
duration of antibiotic administration. The risk is probably low for bacteria
considered highly susceptible to antimicrobial agents, such as methicillin-susceptible Staphylococcus aureus or Haemophilus
influenzae, but might be high for certain species, especially Pseudomonas aeruginosa, which is particularly difficult
to eradicate from the respiratory tract.18,19 Thus,
at present, a short-term regimen is rarely prescribed, despite the potential
major advantages it could have in terms of bacterial ecology and prevention
of the emergence of multiresistant strains in the ICU.

Results obtained with various antibiotic strategies investigated in
patients with VAP are difficult to assess because the diagnosis of pulmonary
infection in this setting is difficult; thus, the populations studied are
often ill defined, including patients with various lower respiratory tract
infections, ranging from tracheobronchitis to severe pneumonia.16,17 The
use of invasive diagnostic techniques, such as fiberoptic bronchoscopy, coupled
with quantitative cultures of distal pulmonary secretions obtained with a
protected specimen brush, bronchoalveolar lavage, or both, might more precisely
identify patients with VAP and more accurately select patients for inclusion
in clinical trials.20- 22 We
therefore undertook a randomized trial to compare the outcomes of therapy
with an 8-day or 15-day antibiotic regimen for a well-defined group of ICU
patients who had developed VAP, as confirmed by quantitative culture results
of bronchoscopic specimens.

METHODS

Study Design and Organization

This randomized, double-blind (until day 8) trial was performed on 2
parallel groups in 51 ICUs in France (Figure
1). The protocol was approved by the Comité Consultatif de
Protection des Personnes dans la Recherche Biomédicale of Hôpital
Saint-Louis, Paris, France, in May 1999. All patients or their relatives gave
written informed consent before enrollment.

Figure 1. Patient Flow Diagram

Patients

The ICU patients who were intubated and had received mechanical ventilation
for at least 48 hours were eligible for the study if they met all the following
criteria: (1) older than 18 years; (2) clinical suspicion of VAP, defined
by a new and persistent infiltrate on chest radiography associated with at
least 1 of the following: purulent tracheal secretions, temperature of 38.3°C
or higher, and a leukocyte count higher than 10 000/µL (for patients
experiencing acute respiratory distress syndrome and for whom it was difficult
to demonstrate deterioration of radiologic images, at least 1 of the 3 preceding
criteria sufficed for inclusion); (3) positive quantitative cultures of distal
pulmonary secretion samples, obtained by fiberoptic bronchoscopy, of bronchoalveolar
lavage fluid (significant threshold ≥104 colony-forming units/mL),
or with a protected specimen brush or catheter (significant threshold ≥103 colony-forming units/mL)23; and (4)
instigation within the 24 hours following bronchoscopy of appropriate empirical
antibiotic therapy directed against the microorganism(s) responsible for the
pulmonary infection, as determined by their susceptibility patterns.24

Patients were excluded if they (1) were pregnant; (2) were enrolled
in another trial; (3) had little chance of survival, as defined by a Simplified
Acute Physiology Score (SAPS II) of more than 65 points; (4) had neutropenia
(leukocyte counts <1000/µL or neutrophils <500/µL); (5)
had concomitant acquired immunodeficiency syndrome (stage 3 according to the
Centers for Disease Control and Prevention 1993 classification); (6) had received
immunosuppressants or long-term corticosteroid therapy (≥0.5 mg/kg per
day for >1 month); (7) had a concomitant extrapulmonary infection diagnosed
between days 1 and 3 that required prolonged (>8 days) antimicrobial treatment;
or (8) their attending physician declined to use full life support. Patients
who had early onset pneumonia (within the first 5 days of mechanical ventilation)
and no antimicrobial therapy during the 15 days preceding infection were also
excluded because the causative pathogens in such a setting are usually highly
sensitive to antibiotics.16,25

Randomization

Patients were randomly assigned to receive antibiotics for 8 or 15 days
3 days after the bronchoscopy, as soon as it was possible to verify that the
inclusion or exclusion criteria had been met and that the pathogens isolated
at significant concentrations by quantitative cultures of bronchoscopic specimens
were appropriately covered by the initial empirical antibiotic regimen selected
on day 1 (defined as the day of bronchoscopy), based on the results of antibiograms.
Randomization was performed centrally, using an interactive voice system,
and stratified by center in blocks of 4 according to a computer-generated
random-number table. In order not to influence antibiotic prescriptions, the
randomization assignment was not communicated to the investigators until day
8; thus, all patients, medical and nursing staffs, and pharmacists remained
blinded until then. On that day, investigators had to telephone the randomization
center to receive the treatment assignment by fax. If this call was not made
before 3 PM, a fax was automatically sent by the randomization
center to remind the investigator to call.

Antibiotic Treatments

Drug selection was left to the discretion of the treating physicians,
including any adaptation considered necessary as a function of the definitive
microbiologic results identifying the pathogen(s) and its susceptibility patterns.
Nevertheless, it was specified in the protocol that the initial empirical
antibiotic regimen (ie, before the susceptibility patterns of the responsible
microorganisms were known) should preferably combine at least an aminoglycoside
or a fluoroquinolone and a broad-spectrum betalactam antimicrobial agent,
unless the microorganism(s) was not considered to be sensitive to these classes
or a contraindication to their use was present, as recommended by the American
Thoracic Society.16 Investigators were strongly
encouraged to convert this initial regimen into a narrow-spectrum therapy,
based on culture results, which in all cases were obtained within 48 to 72
hours after bronchoscopy. All antibiotics were withdrawn, either at the end
of day 8 or day 15, according to the randomization assignment, except those
prescribed for a documented pulmonary infection recurrence before that day
or for an infection predating VAP, when its total duration of treatment was
considered insufficient, for example, endocarditis. In that situation, only
the antibiotics prescribed before inclusion were continued and those prescribed
for the VAP episode were stopped.

The following baseline variables were recorded before randomization
(Table 2): numbers and types of
microorganisms responsible for pneumonia (only those recovered at significant
concentrations from bronchoscopic specimens were considered to be responsible
for pulmonary infection); duration of prior mechanical ventilation; use of
any antibiotics before VAP onset; SAPS II; ODIN score; SOFA score; temperature;
leukocyte count; ratio of the partial pressure of arterial oxygen to the fraction
of inspired oxygen (PaO2/FIO2); radiologic score (range,
0-12 according to the density of pulmonary infiltrate[s])13;
bacteremia; presence of shock, defined as systolic arterial pressure lower
than 90 mm Hg with signs of peripheral hypoperfusion or need for continuous
infusion of vasopressor or inotropic agents30;
and presence of the acute respiratory distress syndrome, defined as a generalized
pulmonary infiltrate, PaO2/FIO2 less than 200, and the
absence of clinical evidence of left atrial hypertension.31

Table Graphic Jump LocationTable 2. Baseline Characteristics of the Study
Patients as a Function of the Duration of Antibiotic Administration*

Follow-up and Definitions

The following data were recorded daily during the 28-day period after
the initial bronchoscopy: temperature; leukocyte counts; PaO2/FIO2; presence or absence of purulent tracheal secretions; patient's mechanical
ventilation status; vital signs; and ODIN score. The SOFA and radiologic scores
were determined again on days 3, 7, 14, 21, and 28. Extreme vigilance for
pneumonia recurrence was maintained throughout the study to detect any possible
relapse or new episode of pulmonary infection, and fiberoptic bronchoscopy
was performed before the introduction of any new antibiotics as soon as a
patient became febrile, had purulent tracheal secretions, a new pulmonary
infiltrate developed, or an existing infiltrate progressed. Distal pulmonary
secretions were also collected bronchoscopically when unexplained hemodynamic
instability required higher vasopressor doses (>30%) or their introduction;
in the case of unexplained deterioration of blood gases, with a PaO2/FIO2 decrease of more than 30%; or when an intercurrent
event imposed an urgent change of antibiotic therapy, regardless of the reason.
Any antibiotic use was recorded daily until day 28. In addition, the patient's
status at discharge from the hospital and 60 days after bronchoscopy was recorded.

Patients were considered to have microbiologically documented recurrent
pulmonary infection when at least 1 bacterial species grew at a significant
concentration from samples collected during a second bronchoscopy. Recurrence
was considered a relapse if at least 1 of the initial causative bacterial
strains (ie, same genus, species, and serotype when available) grew at a significant
concentration from a second distal sample; otherwise, it was considered to
be a superinfection. Multiresistant bacteria were defined as 1 of the following:
ticarcillin-resistant P aeruginosa, Acinetobacter baumannii, or Stenotrophomonas maltophilia; extended-spectrum betalactamase-producing Enterobacteriaceae; and
methicillin-resistant S aureus. We calculated the
number of antibiotic-free days as the number of days during the 28 days after
living patients had been randomized and had not received any antibiotic.32 Using the same method, we determined the number of
mechanical ventilation–free days and the number of organ failure–free
days, as defined by the ODIN score.

Outcome Measures

The primary outcome measures were death from any cause; microbiologically
documented pulmonary infection recurrence, defined using the same microbiologic
criteria as those that led to patient inclusion in the trial; and antibiotic-free
days, all of which were assessed 28 days after the first bronchoscopy for
suspected VAP onset.

Secondary outcome measures were the number of mechanical ventilation–free
days; the number of organ failure–free days; the evolution of the 6
parameters comprising the SOFA and the ODIN scores from day 1 to day 28; the
evolution of signs and symptoms potentially linked to pulmonary infection,
including fever, leukocyte counts, PaO2/FIO2,and radiologic
score; the length of stay in the ICU; the rate of unfavorable outcomes, defined
as death, infection recurrence, or prescription of a new antibiotic for any
reason provided that this new treatment lasted longer than 48 hours; mortality
at day 60; in-hospital mortality; and the percentage of emerging multiresistant
bacteria during the ICU stay, as assessed by microbiologic examination of
all bronchoscopic samples collected for pulmonary infection recurrence.

Statistical Analyses

The trial was designed to demonstrate the noninferiority of the 8-day
vs the 15-day regimen in terms of death and pulmonary infection recurrence
rates, and its superiority in terms of antibiotic use, as assessed by the
number of days alive and antibiotic-free. Owing to the objective of noninferiority
for the first 2 end points and to potentially include fewer patients and shorten
the duration of the trial, a repeated 1-sided, 100 × (1 –α)–percent
confidence interval (CI) approach was used for planning and monitoring the
study, with the α risk being set at 10%.33 To
test for noninferiority with an α risk of 10%, 200 patients were required
for each group to achieve a power of 90% to exclude a 10% difference between
the 2 groups, assuming respective death and recurrent pulmonary infection
rates of 40% and 25% for the 15-day regimen. This sample was also sufficiently
large to ensure the detection of a 20% lower mean number of antibiotic-free
days for patients assigned to the 8-day regimen, assuming a mean (SD) of 10
(5) antibiotic-free days for the group treated for 15 days (α = .05, β
= .02). Thus, in this noninferiority trial, using 90% CIs around the estimate
of effect, criteria are met for noninferiority if the upper limit of the CI
is less than 10% (the prespecified clinically acceptable difference, δ)
for mortality and pulmonary infection recurrence.

Statistical analysis was based on the intention-to-treat principle.
SAS 8.2 software (SAS Inc, Cary, NC) was used for statistical analyses. Each
of the 4 planned interim analyses was conducted after the inclusion of 100
consecutive patients. At each analysis, repeated 1-sided 90% CIs were calculated
for the percentage point differences between death and pulmonary infection-recurrence
rates for patients treated with 8 or 15 days of antibiotics, according to
the method described by Jennison and Turnbull34 and
Fleming et al.35 Conversely, the difference
in the numbers of antibiotic-free days between the 2 randomized groups was
analyzed using the nonparametric Wilcoxon test and calculation of 95% CIs
for the mean difference between the groups. The independent Main End Point
and Safety Monitoring Committee met after each of the planned 4 interim analyses
to decide whether the study should be continued or stopped. A decision to
stop the trial could be made if and only if (1) the upper limit of the CI
was less than 10% for the 2 primary end points used to evaluate noninferiority—ie,
mortality and pulmonary infection recurrence and (2) the superiority of the
8-day vs 15-day regimen on the number of antibiotic-free days was demonstrated,
on the basis of a significance level defined as α risk/4 or less, using
a conventional α risk for comparative studies of 5%.

To define further the prognostic importance of duration of antimicrobial
therapy and other baseline variables, logistic regression analysis was applied
to the outcomes of death and pulmonary infection recurrence. The consistency
of treatment effects within each center or key baseline characteristics, such
as the type of responsible microorganism (segregating between nonfermenting
gram-negative bacilli [ie, P aeruginosa, A baumannii, and S maltophilia]), methicillin-resistant S aureus, and other pathogens), was evaluated using the
Gail and Simon test.36 Cumulative-event curves
were estimated with the Kaplan-Meier method. Statistical analyses of secondary
end points were based on the use of conventional 1-sided 90% CIs.

Baseline characteristics of patients were compared with the unpaired t test or the Wilcoxon rank sum test for continuous variables,
depending on their distributions. Percentage differences were compared with
the Fisher exact test (or the χ2 test, when appropriate).

RESULTS

Characteristics of the Patients

A total of 402 patients were enrolled in the study between May 1999
and June 2002; one subsequently withdrew his consent to receive a randomly
assigned treatment and for use of his data, leaving 401 patients: 197 in the
8-day group and 204 in the 15-day group (Figure 1). The clinical characteristics of these 401 patients at
admission (Table 1) and at baseline
(Table 2) were similar, except
that the percentage of female patients was slightly but significantly higher
(P = .046) for the group receiving 15 days of antibiotics
(Table 1).

Microorganisms considered responsible for VAP are listed in Table 3. Nonfermenting Gram-negative bacilli
and methicillin-resistant S aureus were isolated,
respectively, from 64 (32.5%) and 22 (11.2%) potentially polymicrobial episodes
that were treated with 8 days of antibiotics compared with 63 (30.9%) and
23 (11.3%) infections that were treated with a 15-day regimen (P = .67 and P = .99, respectively).

No statistically significant between-group differences were found among
the agents used during the first 8 days of the study. A regimen combining
an aminoglycoside or a fluoroquinolone plus a betalactam was prescribed on
day 1 to 179 (90.9%) of 197 patients in the 8-day group compared with 187
(91.7%) of 204 patients in the 15-day group (P =
.86); on day 8, those values were 63 (32.8%) of 192 in the 8-day group and
63 (39.2%) of 199 in the 15-day group (P = .21).
Thirty-nine percent of patients in the 8-day group and 37% in the 15-day group
received vancomycin on the first day of the study (P =
.61).

Primary Outcomes

Twenty-eight days after VAP onset, 37 (18.8%) of 197 patients in the
8-day group and 35 (17.2%) of 204 patients in the 15-day group had died (Table 4). The absolute difference was 1.6%,
with the 90% CI for the between-group difference ranging from −3.7%
to 6.9%. Repeated bronchoscopic specimens for clinically suspected recurrence
or other reasons were obtained from 120 patients (60.9%) in the 8-day group
(for a total of 188 bronchoscopies) and 93 patients (45.6%) in the 15-day
group (for a total of 158 bronchoscopies; P = .003).

Table Graphic Jump LocationTable 4. Primary Study Outcomes 28 Days After
Bronchoscopy as a Function of Duration of Antibiotic Administration

Based on quantitative culture results, the microbiologically documented
pulmonary infection-recurrence rate was 28.9% of patients receiving the 8-day
regimen and 26% of those taking antibiotics for 15 days, with an absolute
difference of 2.9% (90% CI, −3.2% to 9.1%; Table 4). Thus, the noninferiority of the 8-day regimen was retained.
The percentages of pulmonary infection recurrences considered to be relapses
were similar for the 2 groups (16.8% among the 8-day vs 11.3% among the 15-day
regimen groups [absolute difference, 5.5%; 90% CI, 0.7%-10.3%]), as were the
percentages of those considered to be superinfections (19.8% among the 8-day
vs 18.6% in the 15-day groups [absolute difference, 1.2%; 90% CI, −4.3%
to 6.6%]; Table 4).

As estimated with the Kaplan-Meier method using a log-rank test, survival
rates were similar (Figure 2). Also
similar were the mean (SD) times to pulmonary infection recurrence: 21.6 (0.5)
days for the 8-day and 22.5 (0.5) days for the 15-day treatment groups (P = .38); times to relapse: 23.8 (0.5) days and 24.1 (0.4)
days (P = .12); and times to the development of superinfections:
22.8 (0.5) and 23.8 (0.5) days (P = .65).

Figure 2. Kaplan-Meier Estimates of the Probability
of Survival

Probability of survival is for the 60 days after ventilator-assisted
pneumonia onset as a function of the duration of antibiotic administration.

In contrast, the patients who received antibiotics for 8 days had significantly
more mean (SD) antibiotic-free days (13.1 [7.4] vs 8.7 [5.2] days, P<.001), and significantly more broad-spectrum (imipenem, piperacillin-tazobactam,
ticarcillin-clavulanic acid, cefepime, cefpirome, ceftazidime, or ciprofloxacin)
antibiotic-free days (18.4 [8.0] vs 15.3 [8.4] days; P =
.01). As shown in Table 5, there
were no significant differences between the 2 groups in the numbers of patients
for whom antibiotics were continued after the end of the randomly assigned
regimen or the numbers of patients who received an additional course of antibiotics.

Logistic regression-based adjustment of the baseline variables listed
in Table 1 and Table 2 did not substantially modify these findings. The adjusted
risk ratio for death of patients in the 8-day regimen vs those in the 15-day
regimen was 1.2 (95% CI, 0.6-2.1) after adjustment for age, sex, McCabe and
Jackson classification, admission category, duration of mechanical ventilation
before VAP onset, site and severity of organ/system failure based on the SOFA
score at baseline, bacteremia, and type(s) of pathogens responsible for VAP.
The adjusted risk ratio for recurrent pulmonary infection was 1.2 (95% CI,
0.8-2.1). No significant interactions could be established between treatment
assignment and any covariate, particularly between the types of pathogens
responsible for VAP and the treatment group with respect to the 3 primary
outcome measures (Table 4). However,
for primary infections caused by nonfermenting Gram-negative bacilli, a higher
percentage of patients developed documented pulmonary infection recurrence
in the 8-day group than in the 15-day group (40.6% vs 25.4%; risk difference,
15.2%; 90% CI, 3.9%-26.6%, respectively); 21 of 26 and 12 of 16 in the respective
groups experienced relapse (Table 4).

Secondary Outcomes

None of the secondary outcome measures listed in Table 6 or the observed changes of fever, leukocyte count, PaO2/FIO2, or organ dysfunction and radiologic scores from day
1 through day 28 (Figure 3) differed
significantly between patients in the 8-day or 15-day groups. The 2 groups
also had similar mean (SD) number of days without cardiovascular failure (21.4
[9.3] vs 21.0 [9.3] days), hematologic failure (25.4 [6.3] vs 25.5 [6.0] days),
hepatic failure (25.0 [6.8] vs 24.9 [6.8] days), neurologic failure (24.1
[7.5] vs 24.6 [6.9] days), and renal failure (23.8 [8.0] vs 22.6 [9.2] days).
Ninety-one patients (46.2%) in the 8-day group and 89 patients (43.6%) in
15-day group had unfavorable outcomes. As reported in Table 6, none of the secondary outcome events—mortality at
days 28 and 60, number of organ failure–free days, number of mechanical
ventilation–free days, length of ICU stay, and unfavorable outcome rate—was
higher for patients with VAP caused by nonfermenting gram-negative bacilli
and treated for 8 days although they did have a slightly higher rate of recurrence
(Table 4). Notably, among patients
who developed recurrent pulmonary infections, multiresistant pathogens emerged
significantly less frequently in those who had received 8 days of antibiotics
(42.1% vs 62.3% of recurrent infections; P = .04).

COMMENT

In this large, multicenter, randomized, double-blind (until day 8) clinical
trial, we observed no benefit to prolonging antibiotics to 15 days from an
8-day regimen, for patients with VAP for whom strict bronchoscopic criteria
had been applied to diagnose pulmonary infection and who received appropriate
initial empiric antimicrobial treatment. The CIs for the between-group differences
in mortality and pulmonary infection-recurrence rates exclude an absolute
difference exceeding 10% in favor of the 15-day regimen. No differences in
other outcome parameters could be established, including the duration of mechanical
ventilation, the number of organ failure–free days, the evolution of
signs and symptoms potentially linked to pulmonary infection, the duration
of ICU stay, and mortality rates on day 60 or status at hospital discharge.
The rates of unfavorable outcomes, defined as death, infection recurrence
or prescription of a new antimicrobial treatment during the study period,
were also similar for the 2 groups.

We also found that the average number of antibiotic-free days from day
1 to day 28 was 50% higher for patients who had been randomized to the 8-day
regimen than for patients assigned to the 15-day regimen, thereby emphasizing
that such a strategy could effectively lower the exposure of ICU patients
with VAP to any unnecessary antimicrobial therapy after randomization. Pertinently,
multiresistant pathogens emerged more frequently for patients with pulmonary
infection recurrence who had received 15 days of antibiotics. These results
are consistent with those of other observational studies conducted on ICU
patients that clearly demonstrated a direct relationship between the use of
antimicrobial agents and increased resistance of Enterobacteriaceae and other
pathogens.2- 4,6,37,38 Although
appropriate antibiotics may improve the survival rate of patients with VAP,
their indiscriminate use in treating ICU patients without infection should
probably be discouraged.5,10,32

It is widely accepted that nonfermenting gram-negative bacilli, especially P aeruginosa, are difficult to eradicate from the respiratory
tract and that the risk of therapeutic failure or relapse, defined as the
reappearance of signs of pneumonia and isolation of the same pathogen(s) that
have acquired resistance or not, is high in such a setting.18,19,39 In
our study, slightly more patients with nonfermenting gram-negative bacilli
assigned to the 8-day regimen had pulmonary infection recurrences and we were
unable to demonstrate the noninferiority of this regimen for this end point
compared with the 15-day course, either because of the relatively small number
of studied patients or because the shorter duration of treatment leaves patients
vulnerable to more pulmonary infection recurrences. However, despite this
higher recurrence rate, neither the mortality nor unfavorable outcome rate
was higher for patients with VAP caused by those pathogens when their antimicrobial
therapy lasted only 8 days. Therefore, pending the results of studies directly
evaluating this point, we believe that 8 days of antibiotics could be safely
implemented for all patients with VAP, including those with infections caused
by nonfermenting gram-negative bacilli, provided that extreme vigilance be
maintained after cessation of antimicrobial therapy and fiberoptic bronchoscopy
be performed as soon as possible when relapse is suspected, as was the case
in this study.

To the best of our knowledge, only a few studies have assessed the optimal
duration of antimicrobial therapy in patients with VAP.24,40,41 In
a recent cohort study of 102 consecutive patients with VAP prospectively evaluated
before and after the application of a clinical guideline restricting the total
duration of antibiotics to 7 days for selected patients (those who were neither
bacteremic nor neutropenic and who became afebrile under therapy), no statistically
significant differences in hospital mortality rates and durations of hospitalizations
were found between the 2 study groups; however, in contrast to our results,
after-group patients whose mean duration of treatment was 7 days, were less
likely to develop a second episode of VAP compared with those in the before
group.24 That study evaluated not only the
implementation of a new therapeutic protocol but also new measures for VAP
prevention, which could explain why a lower rate of VAP recurrences was documented
during its second part.

This trial is limited by uncertainty about the potential effect of its
unblinded design. A more rigorous design would have been to use a double-blind
scheme throughout the entire study—ie, from day 1 to day 28. However,
insofar as the choice of antibiotics was left to the treating physician, the
use of a placebo for each of the drugs that was prescribed would have posed
insurmountable technical and logistical problems. Furthermore, because of
the necessity to be able to adapt the dosages of certain antibiotics as a
function of their plasma concentrations, the "blind" aspect of the study would
obviously have no longer existed for certain patients. However, investigators
were not aware of the duration of antibiotics until day 8 and every effort
was made to standardize patient follow-up, using rigorous criteria to evaluate
their outcome.

The second limitation is that a relatively large subset of ICU patients,
as indicated on the flow-chart (Figure 1),
was excluded from our study, especially those with early-onset pneumonia who
had not received previous antibiotics, those who were severely immunocompromised,
those who had little chance of survival (as defined by a SAPS II >65) and,
most importantly, those for whom the initial empirical antimicrobial therapy
was not appropriate, as determined by the susceptibility patterns of the causative
microorganisms. In addition, the diagnosis of pulmonary infection had to be
confirmed by significant (>103 or >104 colony-forming
units/mL) quantitative culture results of bronchoscopic specimens to avoid
the inclusion of patients with less severe forms of respiratory-tract infection,
such as tracheobronchitis. Thus, the results of this study cannot necessarily
be extended to other ICU populations, which we did not evaluate.

Finally, it is important to acknowledge that our trial was not designed
to directly test the hypothesis that 8 days of antibiotics for patients with
VAP is superior to a 15-day regimen, in terms of minimizing adverse drug effects,
or in documenting its cost effectiveness. We did not conduct a formal cost-benefit
study.

In summary, for ICU patients who develop microbiologically proven VAP,
we found no clinical advantage of prolonging antimicrobial therapy to 15 days
compared with 8 days. The diverse clinical characteristics and reasons for
mechanical ventilation among patients enrolled in this trial and the consistency
of the results suggest that our conclusions may be applicable to many critically
ill patients who develop VAP, with the possible exception of immunocompromised
patients, those whose initial empiric antimicrobial treatment was not appropriate
for the causative microorganisms, and those whose infections were caused by
a nonfermenting gram-negative bacillus, including P aeruginosa. Such an approach could help control health care costs and contain
the emergence of bacterial resistance in the ICU.

Goldmann DA, Weinstein RA, Wenzel RP.
et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant
microorganisms in hospitals: a challenge to hospital leadership. JAMA.1996;275:234-240.PubMed

Goldmann DA, Weinstein RA, Wenzel RP.
et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant
microorganisms in hospitals: a challenge to hospital leadership. JAMA.1996;275:234-240.PubMed

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the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.

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